The present invention relates to the use of pterins to increase the in-vivo and in-vitro activity of lymphokines and other blood factors.
Lymphokines are specific substances secreted by lymphocytes in reaction to antigen stimulation. Considered to be intermediates in cell-mediated immunity, they also play a significant part in inflammations, etc. They are not antibodies, but biologically highly active factors (hormones) that are receptor-specific to preferred target cells. Interleukin-2, interleukin-3, CSF (colony-stimulating factor), and B-cell factors, for example, are lymphokines. Since the concepts of immunology, including that of "lymphokines," are always changing as the result of new knowledge, the term "other blood factors" is also to be understood as being included therein.
Interleukin-2, abbreviated IL-2 and previously also called T-cell growth factor (TCGF) (Aarden, L.A. et al., "Revised nomenclature for antigen-nonspecific T-cell proliferation and helper factors," J. Immunology 123 [1979], 1928-2929; and Morgan, D. A., Ruscetti, F. W., and Gallo, R. C., "Selective in vitro growth of T lymphocytes from normal human bone marrow," Science 193 [1976], 1007), is a glycoprotein with a molecular weight of about 15 000 and an isoelectric point in the neutral range (Gillis, S., Mochizuki, D. Y., Coulon, P. J., Hefeneider, S. H., Rambthun, C. A., Gillis, A. E., Frank, M. B., Henney, C. S., & Watson, J. D., "Molecular characterization of interleukin-2," Immunolog. Rev. 63 [1982], 167-209). Its occasionally described molecular heterogeneity is ascribed to differences in glycosylation (Robb, R. J. & Smith, K. A., "Heterogeneity of human T-cell growth factor due to variable glycosylation," Molecular Immunol. 18 [1981], 1087-1094).
IL-2 is considered the "second signal" in immunoresponse (Ruscetti, F. W. & Gallo, R. C., "Human T-lymphocyte growth factor: regulation of growth and function of T lymphocytes," Blood 57 [1981], 379-394; Wagner, H., Hardt, C., Heeg, K., Pfitzenmaier, K., Solbach, W., Bartlet, R., Stockinger, H., & Rollinghoff, M., "In vivo and in vitro effects of interleukin-2", Immunol. Rev. 51 [1980], 215-236) and represents a regulation factor that makes it possible to continuously cultivate normal activated and neoplastic T cells in vitro. Among the effector cells that can be cloned and cultured over the long term with the addition of IL-2 preparations are T-helper and suppressor cells, cytotoxic T cells, and natural killer cells (NKC's).
Many disruptions of the immunodefense system (immunological diseases) can be ascribed to the lack of cells that produce interleukin-2, to inadequate IL-2 production, or to insufficient formation of IL-2 eptors, and can in many cases be improved by prescribing interleukin-2.
More recent studies have also demonstrated that the production of interleukin-2 decreases greatly with age. Interleukin-2 is accordingly an available therapeutic means for curing or moderating diseases that are caused by disruptions in its own production.
Interleukin-2 can also be employed in cancer therapy.
Pterins are described in the literature as animal pigments, as cofactors (tetrahydrobiopterin) in the hydroxylation of tryptophan, phnenylalanine, and tyrosine (with absence leading to serious neurological defects and hyperphenylalaninemia), as regulators of cell proliferation (partial replacement of fetal calf serum), and as factors that exert an effect on the immunosystem (Rompps, Chemie Lexikon, 7th ed., 2831-2832; Milstein, S. & Kaufman, S., "Tetrahydro-sepiapterin as an intermediate in tetrahydrobiopterin biosynthesis," Biochemical and Biophysical Research Communications 115, 3 [Sept. 30, 1983], 888-893; Ziegler, I., Hamm, U., & Berndt, I., "Participation of pterins in the control of lymphocyte stimulation and lymphoblast proliferation," Cancer Research 42 [1983], 5356-5359); Ziegler, I., Schwulera, U., Sonneborn, M. H., Muller, W. J. P. "Modulation of Interleukin-2 activity by lymphocyte-derived tetrahydro biopterin," Naturwissenschaften 72 (1985), 330-331.
The biological detection of lymphokines is often very difficult if they are present in very small amounts, and makes diagnosis difficult. It is also considered worth attempting to increase the effectiveness of lymphokines in therapeutic applications.